Microwave enhanced reduction of nitro and azido arenes to N-arylformamides employing Zn-HCOONH4: Synthesis of 4(3H)-quinazolinones and pyrrolo[2,1-c][1,4]benzodiazepines

Article abstract of DOI:10.1016/j.tetlet.2004.06.112

Microwave mediated reduction of nitro and azido arenes to N-arylformamides using Zn-HCOONH₄ is described. In the absence of microwave conditions, this methodology affords amines. This protocol has been extended to the synthesis of pyrrolo[2,1-c][1,4]benzodiazepines and 4(3H)-quinazolinones.

Full text of DOI:10.1016/j.tetlet.2004.06.112

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6517–6521
Microwave enhanced reduction of nitro and azido arenes to
N-arylformamides employing Zn–HCOONH4: synthesis of
4(3H)-quinazolinones and pyrrolo[2,1-c][1,4]benzodiazepines
Ahmed Kamal,* K. Srinivasa Reddy, B. Rajendra Prasad, A. Hari Babu
and A. Venkata Ramana
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 31 March 2004; revised 8 June 2004; accepted 18 June 2004
Available online 20 July 2004
Abstract—Microwave mediated reduction of nitro and azido arenes to N-arylformamides using Zn–HCOONH4 is described. In the
absence of microwave conditions, this methodology affords amines. This protocol has been extended to the synthesis of pyrrolo[2,1-
c][1,4]benzodiazepines and 4(3H)-quinazolinones.
Ó 2004 Elsevier Ltd. All rights reserved.
N-Arylformamides have been widely used in the synthe-
sis of biologically active compounds, such as chemothera-
peutic and antibacterial agents1,2 and precursors for the
synthesis of isocyanides.3 They are also found to cata-
lyze the allylation of carbonyl compounds in solution
phase4a as well as in the solid phase.4b Several methods
have been reported for the synthesis of N-arylforma-
mides including the formylation of anilines5a or direct
conversion of nitroarenes with Pd/C and ammonium
formate,5b tin in the presence of toluene/formic acid,5c
iron/formic acid5d and reductive N-formylation of azido
arenes under catalytic transfer hydrogenation condi-
tions.5e Despite their usefulness, most of these methods
have some drawbacks with regard to their long reaction
times, vigorous reaction conditions and the expensive
and sensitive nature of the reagent system. Hence, there
is a continuing requirement to explore practical method-
ologies for the preparation of N-arylformamides. In
continuation of our interest in the total synthesis of nat-
ural products, we wish to report an efficient and solvent-
free reductive N-formylation of nitro and azido arenes
(1, 2) to N-arylformamides 3 with zinc and ammonium
formate under microwave irradiation conditions
(Scheme 1).
Microwave-assisted organic synthesis has recently
gained importance in synthetic organic chemistry6 and
is known to provide several advantages such as reduc-
tion in reaction times, improved yields and cleaner work
up.7 As observed from the results in Table 1, the nitro
and azido arenes have been converted to their corre-
sponding N-arylformamides by employing zinc and
ammonium formate under microwave irradiation. Other
functional groups such as hydroxyl and halogens were
not affected under these reaction conditions.
Employing this procedure, 2-substituted azido- or nitro-
benzoic acids were converted to pharmaceutically
Zn/HCOONH4
Zn/HCOONH4
Ar NO2
Ar NHCHO
Ar N3
MW, 300 W
MW, 300 W
1
3
2
Scheme 1.
Keywords: Zinc; Ammonium formate; Azides; Nitroarenes; N-Arylformamides; Microwave; 4(3H)-Quinazolinones; Pyrrolo[2,1-c][1,4]benzodiaze-
pines.
*
Corresponding author. Tel.: +91-40-27193157; fax: +91-40-27193189; e-mail addresses: ahmedkamal@iict.res.in; ahmedkamal@ins.iictnet.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.112

6518
A. Kamal et al. / Tetrahedron Letters 45 (2004) 6517–6521
Table 1. Conversion of azides and nitroarenes to N-arylformamides under microwave irradiation
Entry
a
Substrate (1, 2)
Product 3a,b
NHCHO
Timec (min)
3.0
Yieldd (%)
80
NO2
NO2
NHCHO
Cl
b
c
3.5
3.0
75
80
Cl
NO2
NHCHO
Cl
Cl
NO2
NHCHO
d
3.0
80
CH3
CH3
NO2
NHCHO
e
f
3.0
2.0
75
84
HO
HO
NO2
NHCHO
H3CO
H3CO
N3
NHCHO
g
2.5
2.5
85
90
N3
NHCHO
h
Cl
Cl
N3
NHCHO
OH
i
j
3.0
2.5
3.0
75
90
77
OH
N3
NHCHO
H3CO
H3CO
N3
NHCHO
CH3
k
CH3
a Mixture of rotamers.
b Products gave satisfactory spectroscopic data (1H NMR, mass).
c Microwave irradiation was performed at 300W with 1min 20s intervals.
d Isolated yields.
important 4(3H)-quinazolinones 6 as shown in Table 2.
The formation of quinazolinones is probably due to the
decomposition of ammonium formate to formamide,
which in turn can condense with the anthranilic acid
(or its ester), which is produced upon reduction. Differ-
ent metals such as Fe and Sn can be used but, amongst
these, Zn has showed remarkable efficiency and has
proved to be an efficient and inexpensive catalyst for
these transformations.8 Recently, 6 has been prepared
from anthranilic acid and formamide under microwave
conditions.9 However, the present study describes, for
the first time, the reductive cyclization of 2-azido/2-
nitrobenzoic acids for the synthesis of 6 under micro-
wave conditions.
azides into amines. This conversion is an important
chemical transformation in synthetic organic chemis-
try, especially for the preparation of nitrogen-containing
heterocycles,10 carbohydrates,11 and in nucleoside
chemistry. A wide variety of reagents including tetra-
thio-molybdate,12a Sm/NiCl2Æ6H2O,12b NaBH4/CoCl2Æ
6H2O,12c Zn/NH4Cl,12d MCM–silyl amine Pd(II)
complex,12e decaborane/Pd/C,12f FeCl3–Zn,12g modified
Staudinger conditions using trimethylphosphine,12h
and NaBH4/tin-bis(1,2-benzenethiolate)12i have been
recently reported. Many of these methods have their
own disadvantages in terms of general applicability,
commercial availability, selectivity, toxicity, and reac-
tion conditions. As a result, there is a continuing
demand to explore simple, efficient, and more conven-
ient methodologies. In our related research pro-
grammes, we have developed some new methodologies
In the absence of microwave irradiation, this reagent
system provides a method for the transformation of

A. Kamal et al. / Tetrahedron Letters 45 (2004) 6517–6521
6519
Table 2. Conversion of 2-azido/2-nitrobenzoic acids to 4(3H)-quinazolinones 6 under microwave irradiation
H
X
Zn/HCOONH4
MW, 300 W
N
N
O
NH2
NH
COOR
COOR
4
5
6
Entry
a
Substrate (4)
Product 6a
Timeb (min)
Yieldc (%)
O
N3
4.0
80
75
NH
COOH
N3
N
O
b
5.0
NH
COOCH3
N
O
NO2
c
6.0
6.5
75
70
NH
O
COOH
N
NO2
d
NH
Cl
COOH
Cl
N
a Products were characterized by 1H NMR and mass spectroscopy.
b Microwave irradiation was performed at 300W with 2min intervals.
c Yield of isolated products.
towards the synthesis of natural products that involve
azide reduction by employing HI,13a FeCl3–NaI,13b or
TMSCl–NaI.13c In continuation of this effort, herein
we report a simple, mild, and efficient method for the
reduction of arylazides 2 to the corresponding arylam-
ines 8 with zinc and ammonium formate. This system
has been investigated for the reduction of aliphatic
and aromatic nitro compounds to amines,14a for the
reductive cleavage of azo compounds,14b for the deoxy-
genation of heteroaromatic-N-oxides14c and for the
chemoselective reduction of aromatic nitro and azo
compounds in ionic liquids.14d After completing
this work, we came across one report on the reduc-
tion of azides to the corresponding amines14e with
this system. However this methodology was not
applied to the DNA interactive pyrrolobenzodiazepine
chemistry.
but most of these have met with varying degrees of suc-
cess having different limitations.16 Recently, we have
been exploring methods based on an azido reductive
cyclization process and in conjunction with these stud-
ies, the present methodology has been explored. This
process provides PBD imines and dilactams in high
yields (Scheme 2).
In conclusion, we have developed a simple, mild, and
solvent-free method for the synthesis of N-arylform-
amides and 4(3H)-quinazolinones by employing Zn
and ammonium formate under microwave irradiation.
Further, this reagent system has also been employed
for the reduction of the azide functionality and for the
synthesis of DNA interactive pyrrolo[2,1-c][1,4]ben-
zodiazepines (PBDs).
Typical procedures––12a: To a stirred solution of 11a
(1mmol) in methanol (10mL) was added zinc
(1.5mmol), followed by ammonium formate (3mmol).
The resulting mixture was stirred at room temperature
until completion of the reaction as indicated by TLC.
The reaction mixture was then filtered through a Celite
pad and diluted with CHCl3. The organic layer was
washed with brine, dried over Na2SO4, and concen-
trated under reduced pressure. The residue thus
obtained was purified by column chromatography on
silica gel (60–120) using ethyl acetate/hexane (9:1) to
afford pure 12a (80% yield).
The results in Table 3 show that this method offers excel-
lent selectivity in the presence of other functionalities
such as halogens, acids, esters, and carbonyl groups.
Moreover, this process is simple and affords various
amines in excellent yields without the use of toxic or
expensive materials under near neutral conditions.
Furthermore, this method has been extended towards
the preparation of the DNA-binding pyrrolo[2,1-
c][1,4]benzodiazepine (PBD) ring system. These com-
pounds covalently bind to DNA in a sequence selective
manner and as such have potential as antitumor agents
and gene targeting drugs.15 A variety of methods have
been investigated for the preparation of this ring system,
Spectral data for compound 12a––1H NMR (CDCl3,
300MHz): d 1.92–2.35 (m, 4H), 3.52–3.95 (m, 3H),

6520
A. Kamal et al. / Tetrahedron Letters 45 (2004) 6517–6521
Table 3. Conversion of azides to amines
Zn/HCOONH4
Ar N3
Ar NH2
CH3OH, rt
2
8
Entry
a
Substrate (2)
Product 8a
Time (min)
15
Yieldb (%)
90
N3
NH2
N3
NH2
b
20
85
H3COC
N3
H3COC
NH2
c
d
e
f
20
18
20
15
15
25
85
85
85
90
90
80
Cl
Cl
N3
NH2
OH
N3
OH
NH2
COOH
COOH
N3
NH2
H3CO
H3CO
H3C
N3
NH2
g
h
H3C
CH2N3
N3
CH2NH2
NH2
H
H
N
i
j
N
30
30
87
85
COOCH3
COOCH3
COOCH3
CH3
O
CH3
O
N3
NH2
H
N
H
N
COOCH3
O
O
CH(SEt)2
CH(SEt)2
NH2
N
N3
k
l
25
30
90
85
N
O
O
CH(SEt)2
CH(SEt)2
BnO
H3CO
N3
O
NH2
BnO
N
N
H3CO
O
a Characterized by spectroscopic data (IR, 1H NMR, mass) and by comparison with authentic samples.
b Isolated yields.
7.22–7.58 (m, 3H), 7.78 (d, 1H, J=4.5Hz), 8.05 (d, 1H,
J=5.2Hz); EIMS: m/z 200 (M+, 100).
ethyl acetate. The organic layer was washed with brine,
dried over Na2SO4, and concentrated under reduced
pressure. The residue thus obtained was purified by col-
umn chromatography on silica gel (100–200 mesh) with
ethyl acetate/hexane (6:4) to afford pure 6a (70% yield).
6a: 2-Azido benzoic acid (4a) (1mmol), zinc (2mmol) and
ammonium formate (10mmol) were taken into a reaction
tube and thoroughly mixed with a glass rod. The resulting
mixture was placed in a domestic microwave oven
(SANYO, model no. BMO 800 TS, 800W, at
2450MHz) and irradiated for 4min at 300W (see Table
2). The reaction mixture was cooled and extracted with
Spectral data for compound 6a––1H NM
R
(CDCl3+DMSO-d6, 300MHz):
d
7.38 (dt, 1H,
J=8.2Hz, 1.5Hz), 7.58 (d, 1H, J=8.2Hz), 7.66 (dt,
1H, J=8.2Hz, 1.5Hz), 7.84 (br s, 1H), 8.15 (dd, 1H,

A. Kamal et al. / Tetrahedron Letters 45 (2004) 6517–6521
6521
R1
R2
N3
O
R1
R2
N3
O
COOCH3
CHO
DIBAL-H, CH2Cl2
-78 0C, 45 min
N
N
9
11
Zn/HCOONH4
CH3OH, rt
Zn/HCOONH4
CH3OH, rt
85-90 %
75-80 %
H
N
O
R1
R2
N
R1
R2
H
H
N
N
O
O
10
12
R2 = H
a)
b)
R1 = H,
R2 = OBn
R1 = OMe,
R1 = OMe,
c)
R2 = OMe
Scheme 2.
J=8.2Hz, 1.5Hz), 12.05 (br s, 1H); EIMS: m/z 146 (M+,
100).
7, 337–340; (c) Rad-Moghadam, K.; Khajavi, M. S. J.
Chem. Res. (S), 1998, 702–703.
10. Smith, S. C.; Heathcock, C. H. J. Org. Chem. 1992, 57,
6379–6380.
11. McDonald, F. E.; Danishefsky, S. J. J. Org. Chem. 1992,
57, 7001–7002.
Acknowledgements
12. (a) Sridhar, P. R.; Prabhu, K. R.; Chandrasekaran, S. J.
Org. Chem. 2003, 68, 5261–5264; (b) Wu, H.; Chen, R.;
Zhang, Y. Synth. Commun. 2002, 32, 189–193; (c)
Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synthesis 2000,
646–650; (d) Lin, W.; Zhang, X.; He, Z.; Jin, Y.; Gong, L.;
Mi, A. Synth. Commun. 2002, 32, 3279–3284; (e) Kantam,
M. L.; Chowadari, N. S.; Rahaman, A.; Choudary, B. M.
Synlett 1999, 1413–1414; (f) Jung, Y. J.; Chang, Y. M.;
Lee, J. H.; Yoon, C. M. Tetrahedron Lett. 2002, 43,
8735–8739; (g) Pathak, D.; Laskar, D. D.; Prajapati, D.;
Sandhu, S. J. Chem. Lett. 2000, 816–817; (h) Nyffeler, P.
T.; Liang, C.-H.; Koeller, M. K.; Wong, C.-H. J. Am.
Chem. Soc. 2002, 124, 10773–10778; (i) Bosch, I.; Costa,
We (K.S.R., B.R.P., A.H.B., and A.V.R.) thank CSIR
(New Delhi) for the award of research fellowships.
References and notes
1. Petit, G. R.; Kalnins, M. V.; Liu, T. M. H.; Thomas, E.
G.; Parent, K. J. Org. Chem. 1961, 26, 2563–2566.
2. Jackson, A.; Meth-Cohn, O. J. Chem. Soc., Chem.
Commun. 1995, 1319.
3. Barton, D. H. R.; Bringman, G.; Motherwell, W. B.
Synthesis 1980, 68–70.
´
´
4. (a) Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59,
6620–6628; (b) Ogawa, C.; Sugiura, M.; Kobayashi, S.
Chem. Commun. 2003, 192–193.
5. (a) Jung, S. H.; Ahn, J. H.; Park, S. K.; Choi, J.-K. Bull.
Korean Chem. Soc. 2002, 23, 149–150; (b) Pratap, T. V.;
Baskaran, S. Tetrahedron Lett. 2001, 42, 1983–1985; (c)
Hrvatin, P.; Sykes, A. G. Synlett 1997, 1069–1070; (d) Lee,
K. Y.; Kim, J. M.; Kim, J. N. Bull. Korean Chem. Soc.
2002, 23, 1359–1360; (e) Reddy, P. G.; Baskaran, S.
Tetrahedron Lett. 2002, 23, 1919–1922.
6. (a) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225–9283; (b) Microwaves in
Organic Synthesis; Loupy, A., Ed.; Wiley-VCH: Wein-
heim, 2002.
7. (a) Varma, R. S. Green Chem. 1999, 1, 43–55; (b) Loupy,
A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacqualt, P.;
A. M.; Martın, M.; Urpı, F.; Vilarrasa, J. Org. Lett. 2000,
2, 397–400.
13. (a) Kamal, A.; Reddy, P. S. M. M.; Reddy, D. R.
Tetrahedron Lett. 2002, 43, 6629–6631; (b) Kamal, A.;
Ramana, K. V.; Ankati, H. B.; Ramana, A. V. Tetrahe-
dron Lett. 2002, 43, 6861–6863; (c) Kamal, A.; Laxman,
E.; Ariffuddin, M. Tetrahedron Lett. 2000, 41, 7743–
7746.
14. (a) Gowda, D. C.; Mahesh, B.; Gowda, S. Indian J. Chem.
2001, 40B, 75–77; (b) Gowda, S.; Abiraj, K.; Gowda, D.
C. Tetrahedron Lett. 2002, 43, 1329–1331; (c) Balicki, R.;
Cybulski, M.; Maciejewski, G. Synth. Commun. 2003, 33,
4137–4141; (d) Khan, F. A.; Dash, J.; Sudheer, Ch.;
Gupta, R. K. Tetrahedron Lett. 2003, 44, 7783–7787; (e)
Srinivasa, G. R.; Nalina, L.; Abiraj, K.; Gowda, D. C.
J. Chem. Res. (S), 2003, 630–631.
´
Mathe, D. Synthesis 1998, 1213–1234; (c) Varma, R. S.
Pure Appl. Chem. 2001, 73, 193–198.
15. Gregson, S. J.; Howard, P. W.; Hartley, J. A.; Brooks, N.
A.; Adams, L. J.; Jenkins, T. C.; Kelland, L. R.; Thurston,
D. E. J. Med. Chem. 2001, 44, 737–748.
16. (a) Kamal, A.; Rao, M. V.; Laxman, N.; Ramesh, G.;
Reddy, G. S. K. Curr. Med. Chem. Anti-Cancer Agents
2002, 2, 215–254; (b) Thurston, D. E.; Bose, D. S. Chem.
Rev. 1994, 94, 433–465.
8. Paul, S.; Nanda, P.; Gupta, R.; Loupy, A. Synthesis 2003,
2877–2881.
9. (a) Alexandre, F.-R.; Berecibar, A.; Besson, T. Tetrahe-
dron Lett. 2002, 43, 3911–3913; (b) Balalaie, S.; Sharifi, A.;
Ahangarian, B.; Kowsari, E. Heterocycl. Commun. 2001,